Nicotine is highly addictive.[13][14] An average cigarette yields about 2 mg of absorbed nicotine; in lesser doses of that order, the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.[15][16][17] This stimulant effect is a contributing factor to the addictive properties of tobacco smoking. Nicotine's addictive nature includes psychoactive effects, drug-reinforced behavior, compulsive use, relapse after abstinence, physical dependence and tolerance.[18]

Beyond addiction, both short and long-term nicotine exposure have not been established as dangerous to adults,[19] except among certain vulnerable groups.[20] At high-enough doses, nicotine is associated with poisonings and is potentially lethal.[17][21] Nicotine as a tool for quitting smoking has a good safety history.[22] There is inadequate research to show that nicotine itself is associated with cancer in humans.[21] Nicotine in the form of nicotine replacement products is less of a cancer risk than smoking.[21] Nicotine is linked to possible birth defects.[23] During pregnancy, there are risks to the child later in life for type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.[22] The use of electronic cigarettes, which are designed to be refilled with nicotine-containing e-liquid, has raised concerns over nicotine overdoses, especially with regard to the possibility of young children ingesting the liquids.[24]

Nicotine is unusual in comparison to most drugs, as its profile changes from stimulant to sedative with increasing dosages, a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969.[33][34] At very high doses it dampens neuronal activity.[35]

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence. Studies have found that these therapies increase the chance of success of quitting by 50 to 70%,[36] though reductions in the population as a whole have not been demonstrated.[37]

Nicotine is frequently used for its performance-enhancing effects on cognition, alertness, and focus.[38] A meta-analysis of 41 double-blind, placebo-controlled studies concluded that nicotine or smoking had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory.[39] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;[40] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (ki=1 nM), which is also the biological target that mediates nicotine's addictive properties.[41] Nicotine has potential beneficial effects, but it also has paradoxical effects, which may be due to its inverted U-shape or pharmacokinetic features.[42]

Limited data exists on the health effects of long-term use of pure nicotine, because nicotine is usually consumed via tobacco products.[44] The long-term use of nicotine in the form of snus incurs a slight risk of cardiovascular disease compared to tobacco smoking[44] and is not associated with cancer.[45][not in citation given] Nicotine is one of the most rigorously studied drugs.[46] The complex effects of nicotine are not entirely understood.[23] Studies of continued use of nicotine replacement products in those who have stopped smoking found no adverse effects from months to several years, and that people with cardiovascular disease were able to tolerate them for 12 weeks.[44] The general medical position is that nicotine itself, in small doses[failed verification], poses few health risks, except among certain vulnerable groups.[20] A 2016 Royal College of Physicians report found "nicotine alone in the doses used by smokers represents little if any hazard to the user".[47] A 2014 American Heart Association policy statement found that some health concerns relate to nicotine.[44] Experimental research suggests that adolescent nicotine use may harm brain development.[21] Children exposed to nicotine may have a number of lifelong health issues.[14] Administration of nicotine to guinea pigs has been shown to cause harm to cells of the inner ear.[48][unreliable medical source?] As medicine, nicotine is used to help with quitting smoking and has good safety in this form.[22]

By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[49][50] By increasing metabolic rate and inhibiting the usual compensatory increase in appetite, the body weight of smokers is lower on average than that of non-smokers. When smokers quit, they gain on average 5–6 kg weight, returning to the average weight of non-smokers.[51]

Human epidemiology studies show that nicotine use is not a significant cause of cardiovascular disease.[52] A 2015 review found that nicotine is associated with cardiovascular disease.[23] A 2016 review suggests that "the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease."[53] Some studies in people show the possibility that nicotine contributes to acute cardiovascular events in smokers with established cardiovascular disease, and induces pharmacologic effects that might contribute to increased atherosclerosis.[53] Prolonged nicotine use seems not to increase atherosclerosis.[53] Brief nicotine use, such as nicotine medicine, seems to incur a slight cardiovascular risk, even to people with established cardiovascular disease.[53] A 2015 review found "Nicotine in vitro and in animal models can inhibit apoptosis and enhance angiogenesis, effects that raise concerns about the role of nicotine in promoting the acceleration of atherosclerotic disease."[54] A 2012 Cochrane review found no evidence of an increased risk of cardiovascular disease with nicotine replacement products.[55] A 1996 randomized controlled trial using nicotine patches found that serious adverse events were not more frequent among smokers with cardiovascular disease.[55] A meta-analysis shows that snus consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not associated with heart attacks.[56] Hence, it is not nicotine, but tobacco smoke's other components which seem to be implicated in ischemic heart disease.[56] Nicotine increases heart rate and blood pressure[57] and induces abnormal heart rhythms.[58] Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.[59] Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).[60] Nicotine does not adversely affect serum cholesterol levels,[52] but a 2015 review found it may elevate serum cholesterol levels.[23] Many quitting smoking studies using nicotine medicines report lowered dyslipidemia with considerable benefit in HDL/LDL ratios.[53] Nicotine supports clot formation and aids in plaque formation by enhancing vascular smooth muscle.[23]

Although there is insufficient evidence to classify nicotine as a carcinogen, there is an ongoing debate about whether it functions as a tumor promoter.[62]In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.[23] There is inadequate research to demonstrate that nicotine is associated with cancer in humans, but there is evidence indicating possible oral, esophageal, or pancreatic cancer risks.[21] Nicotine in the form of nicotine replacement products is less of a cancer risk than smoking.[21] Nicotine replacement products have not been shown to be associated with cancer in the real world.[23]

In pregnancy, a 2013 review noted that "nicotine is only 1 of more than 4000 compounds to which the fetus is exposed through maternal smoking. Of these, ∼30 compounds have been associated with adverse health outcomes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role. Nicotine also has been shown to have significant deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development." It also notes that "abnormalities of newborn neurobehavior, including impaired orientation and autonomic regulation and abnormalities of muscle tone, have been identified in a number of prenatal nicotine exposure studies" and that there is weak data associating fetal nicotine exposure with newborn facial clefts, and that there is no good evidence for newborns suffering nicotine withdrawal from fetal exposure to nicotine.[72]

Nicotine is not safe to use in any amount during pregnancy.[74] Questions exist regarding nicotine use during pregnancy and their potential consequences on fetal growth and mortality.[47] Nicotine negatively affects pregnancy outcomes and fetal brain development.[21] Risks to the child later in life via nicotine exposure during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.[22] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.[75]

Nicotine dependence involves aspects of both psychological dependence and physical dependence, since discontinuation of extended use has been shown to produce both affective (e.g., anxiety, irritability, craving, anhedonia) and somatic (mild motor dysfunctions such as tremor) withdrawal symptoms.[1] Withdrawal symptoms peak in the first day or two[76] and can persist for several weeks.[77] Nicotine has clinically significant cognitive-enhancing effects at low doses, particularly in fine motor skills, attention, and memory. These beneficial cognitive effects may play a role in the maintenance of tobacco dependence.[77]

In animals it is relatively simple to determine if consumption of a certain drug increases the later attraction of another drug. In humans, where such direct experiments are not possible, longitudinal studies can show if the probability of a substance use is related to earlier use of other substances.[83]

In mice nicotine increased the probability of later consumption of cocaine and the experiments permitted concrete conclusions on the underlying molecular biological alteration in the brain.[84] The biological changes in mice correspond to the epidemiological observations in humans that nicotine consumption is coupled to an increased probability of later use of cannabis and cocaine.[85]

In rats cannabis consumption – earlier in life – increased the later self-administration of nicotine.[86] A study of drug use of 14,577 US 12th graders showed that alcohol consumption was associated with an increased probability of later use of tobacco, cannabis, and other illegal drugs.[87]

Nicotine is regarded as a potentially lethal poison.[88] The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.[15][89] However, the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally.[17] Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50 of 127 mg/kg when administered to mice.[90]

It is unlikely that a person would overdose on nicotine through smoking alone. The US Food and Drug Administration (FDA) stated in 2013 that "There are no significant safety concerns associated with using more than one OTCNRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette."[96]

The rise in the use of electronic cigarettes, many forms of which are designed to be refilled with nicotine-containing e-liquid supplied in small plastic bottles, has raised concerns over nicotine overdoses, especially in the possibility of young children ingesting the liquids.[24] A 2015 Public Health England report noted an "unconfirmed newspaper report of a fatal poisoning of a two-year old child" and two published case reports of children of similar age who had recovered after ingesting e-liquid and vomiting.[24] They also noted case reports of suicides by nicotine.[24] Where adults drank liquid containing up to 1,500 mg of nicotine they recovered (helped by vomiting), but an ingestion apparently of about 10,000 mg was fatal, as was an injection.[24] They commented that "Serious nicotine poisoning seems normally prevented by the fact that relatively low doses of nicotine cause nausea and vomiting, which stops users from further intake."[24]

By binding to nicotinic acetylcholine receptors in the brain, nicotine elicits its psychoactive effects and increases the levels of several neurotransmitters in various brain structures – acting as a sort of "volume control."[medical citation needed] Nicotine has a higher affinity for nicotinic receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.[97] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[98]

Nicotine also activates the sympathetic nervous system,[103] acting via splanchnic nerves to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream.

The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine,[108] suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".

Nicotine has a half-life of 1–2 hours. Cotinine is an active metabolite of nicotine that remains in the blood with a half-life of 18–20 hours, making it easier to analyze.[109]

Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6) and FMO3, which selectively metabolizes (S)-nicotine. A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.[110] Under some conditions, other substances may be formed such as myosmine.[111]

Nicotine is a hygroscopic, colorless to yellow-brown, oily liquid, that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60 °C and 210 °C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water-soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C.[114]

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (−)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[115] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.[116]

On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.[116]

Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety.[117] Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae (such as potatoes, tomatoes, and eggplant).[9]

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[118][119] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.

The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.[citation needed]

The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[citation needed]

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (−)-nicotine.[120]

Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a forensic autopsy. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.[121][122] Nicotine use is not regulated in competitive sports programs.[123]

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, presented to the French King,[124] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.[124]

Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[12]

In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.[127] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.[128]

While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with early research showing low dose nicotine patches could be an effective treatment of major depressive disorder in non-smokers.[137] However, the original research concluded that: "Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine's high risk to health, nicotine patches are not recommended for clinical use in depression."[138]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,[139] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[140]

Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.[141][142]

Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson's disease.[143]

^ abcdefgJerry JM, Collins GB, Streem D (2015). "E-cigarettes: Safe to recommend to patients?". Cleve Clin J Med. 82 (8): 521–6. doi:10.3949/ccjm.82a.14054 (inactive 2017-01-20). PMID26270431. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors. Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.12 Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers. However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.CS1 maint: Uses authors parameter (link)

^"Nicotine: Biological activity". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 7 February 2016. Kis as follows; α2β4=9900nM [5], α3β2=14nM [1], α3β4=187nM [1], α4β2=1nM [4,6]. Due to the heterogeneity of nACh channels we have not tagged a primary drug target for nicotine, although the α4β2 is reported to be the predominant high affinity subtype in the brain which mediates nicotine addiction [2-3].

^ abRuffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am J Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID25083822. The knowledge of ΔFosB induction in chronic drug exposure provides a novel method for the evaluation of substance addiction profiles (i.e. how addictive they are). Xiong et al. used this premise to evaluate the potential addictive profile of propofol (119). Propofol is a general anaesthetic, however its abuse for recreational purpose has been documented (120). Using control drugs implicated in both ΔFosB induction and addiction (ethanol and nicotine), ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124).

^Gause, G. F. (1941). "Chapter V: Analysis of various biological processes by the study of the differential action of optical isomers". In Luyet, B. J. Optical Activity and Living Matter. A series of monographs on general physiology. 2. Normandy, Missouri: Biodynamica.